Tissue repair is a very complex event and involves a continuously orchestrated sequence of signals and responses from platelets, fibroblasts, epithelial, endothelial and immune cells. The details of interaction between these signals, which are mainly growth factors and cytokines, have been widely discussed. However, it is still not clear how activated cells at wound sites lessen their activities after epithelialization is completed. Termination of the wound healing process requires a fine balance between extracellular matrix (ECM) deposition and degradation. Maintaining this balance requires highly accurate epithelial‐mesenchymal communication and correct information exchange between keratinocytes and fibroblasts. As it has been reported in the literature, a disruption in epithelialization during the process of wound healing increases the frequency of developing chronic wounds or fibrotic conditions, as seen in a variety of clinical cases. Conversely, the potential stop signal for wound healing should have a regulatory role on both ECM synthesis and degradation to reach a successful wound healing outcome. This review briefly describes the potential roles of growth factors and cytokines in controlling the early phase of wound healing and predominantly explores the role of releasable factors from epithelial‐mesenchymal interaction in controlling during and the late stage of the healing process. Emphasis will be given on the crosstalk between keratinocytes and fibroblasts in ECM modulation and the healing outcome following a brief discussion of the wound healing initiation mechanism. In particular, we will review the termination of acute dermal wound healing, which frequently leads to the development of hypertrophic scarring.

Bacterial infection and poor cell recruitment are among the main factors that prolong wound healing. To address this, a strategy is required that can prevent infection while promoting tissue repair. Here, we have created a silver nanoparticle-based hydrogel composite that is antibacterial and provides nutrients for cell growth, while filling cavities of various geometries in wounds that are difficult to reach with other dressings. Silver nanoparticles (AgNPs) were synthesized by chemical reduction and characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), and inductively coupled plasma-mass spectroscopy (ICP-MS). Using varying concentrations of AgNPs (200, 400, and 600 ppm), several collagen-based silver–hydrogel nanocomposite candidates were generated. The impact of these candidates on wound healing was assessed in a rat splinted wound model, while their ability to prevent wound infection from a contaminated surface was assessed using a rat subcutaneous infection model. Biocompatibility was assessed using the standard MTT assay and in vivo histological analyses. Synthesized AgNPs were spherical and stable, and while hydrogel alone did not have any antibacterial effect, AgNP–hydrogel composites showed significant antibacterial activity both in vitro and in vivo. Wound healing was found to be accelerated with AgNP–hydrogel composite treatment, and no negative effects were observed compared to the control group. The formulations were non-cytotoxic and did not differ significantly in hematological and biochemical factors from the control group in the in vivo study. By presenting promising antibacterial and wound healing activities, silver–hydrogel nanocomposite offers a safe therapeutic option that can be used as a functional scaffold for an acceleration of wound healing.

An evolving field, nanotechnology has made its mark in the fields of nanoscience, nanoparticles, nanomaterials, and nanomedicine. Specifically, metal nanoparticles have garnered attention for their diverse use and applicability to dressings for wound healing due to their antimicrobial properties. Given their convenient integration into wound dressings, there has been increasing focus dedicated to investigating the physical, mechanical, and biological characteristics of these nanoparticles as well as their incorporation into biocomposite materials, such as hydrogel scaffolds for use in lieu of antibiotics as well as to accelerate and ameliorate healing. Though rigorously tested and applied in both medical and non-medical applications, further investigations have not been carried out to bring metal nanoparticle–hydrogel composites into clinical practice. In this review, we provide an up-to-date, comprehensive review of advancements in the field, with emphasis on implications on wound healing in in vivo experiments.

Introduction: Among the many factors that may limit effective wound healing in patients with chronic ulcers, bacterial infection and poor cell recruitment are primary causes that contribute to prolonged healing. Thus, a novel strategy that aims to prevent bacterial infection within the wound, while at the same time providing structural scaffolding that promotes endogenous tissue repair, would be of great interest. Here, we developed a thermo-sensitive silver nanoparticle hydrogel composite as an antibacterial nutritional scaffold for the wound that contains all nutrients required for cell growth while preventing bacterial infection with the ability to fill up all the cavities and void areas in wounds regardless of their geometry. Methods: Silver nanoparticles (AgNPs) were synthesized by chemical reduction. After characterization, silver hydrogel nanocomposite was developed by reconstitution of collagen-based hydrogel powder in a nanoparticle suspension of varying AgNPs concentrations (200, 400, and 600 ppm). The antibacterial activity of the formulations was examined in vitro and in vivo in subcutaneous implant infected model. The wound healing efficacy of the hydrogel nanocomposite was also evaluated using a splinted wound model in rats through comparison of clinical wound measurements and histological assessments. Cytocompatibility assay and biochemical analysis of blood at the end of in vivo wound healing study were performed to evaluate the safety of formulations. Results: The synthesized nanoparticles were spherical and stable. While hydrogel alone did not show any bacterial reduction in vitro, the inhibition of bacterial growth was significant in all silver hydrogel nanocomposites compared to controls (p <0.05) and was dose-dependent, with maximum reduction observed in the 600 ppm group (4.56±0.26 LOG CFU/mL, P<0.001). All concentrations of AgNPs hydrogel composites showed significant antibacterial activity in vivo as well (P<0.0001). Treatment of splinted wounds with AgNPs hydrogel composite resulted in faster wound closure and accelerated wound re-epithelialization. The formulations were non-cytotoxic and did not differ significantly in hematological and biochemical factors from the control group in in vivo study. Conclusions: By presenting promising antibacterial and wound healing activity, silver hydrogel nanocomposite offers a safe therapeutic option that can be used as a functional scaffold for an acceleration of wound healing.

In full-thickness wounds, inflammation, lack of matrix deposition, and paucity of progenitor cells delay healing. As commercially available solid (sheet) scaffolds are unable to conform to wounds of varying shapes and sizes, we previously generated a nutritious, injectable, liquid skin substitute that can conform to wound topography. In combination with adipose micro-fragments as a viable source of progenitor cells, a composite, in situ forming skin substitute was tested for the treatment of silicon ring splinted full-thickness wounds in rats. The in vitro survivability and migratory capacity of adipocytes derived from rat micro-fragmented fat cultured in our scaffold was examined with a Live/Dead assay, showing viability and migration after 7 and 14 days. In vivo, the efficacy of our scaffold alone (LDS) or with adipose micro-fragments (LDS+A) was compared to a standard dressing protocol (NT). LDS and LDS+A showed ameliorated wound healing, including complete epithelialization and less immune cell infiltration, compared to the NT control. Our findings demonstrate that a 3D liquid skin scaffold is a rich environment for adipocyte viability and migration, and that the addition of adipose micro-fragments to this scaffold can be used as a rich source of cells for treating full-thickness wounds.